TY - JOUR
T1 - Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment
AU - Peled, Tony
AU - Shoham, Hadas
AU - Aschengrau, Dorit
AU - Yackoubov, Dima
AU - Frei, Gabi
AU - Rosenheimer G, Noga
AU - Lerrer, Batya
AU - Cohen, Haim Y.
AU - Nagler, Arnon
AU - Fibach, Eitan
AU - Peled, Amnon
N1 - We thank Dr. Nadir Askenasy of the Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel for the critical reading of the manuscript and Mary Clausen, Ido D. Weiss, Katia Beider the Gene Therapy Institute, Hadassah University Hospital, Jerusalem, Israel for technical assistance.
PY - 2012/4
Y1 - 2012/4
N2 - Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34+ cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34+ cells cultured with cytokines. In the presence of NAM, the fraction of CD34+CD38- cells increased and the fraction of differentiated cells (CD14+, CD11b+, and CD11c+) decreased. CD34+ cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD+-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34+ cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34+ cells.
AB - Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34+ cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34+ cells cultured with cytokines. In the presence of NAM, the fraction of CD34+CD38- cells increased and the fraction of differentiated cells (CD14+, CD11b+, and CD11c+) decreased. CD34+ cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD+-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34+ cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34+ cells.
UR - http://www.scopus.com/inward/record.url?scp=84858339102&partnerID=8YFLogxK
U2 - 10.1016/j.exphem.2011.12.005
DO - 10.1016/j.exphem.2011.12.005
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 22198152
AN - SCOPUS:84858339102
SN - 0301-472X
VL - 40
SP - 342-355.e1
JO - Experimental Hematology
JF - Experimental Hematology
IS - 4
ER -
